Aminoacetonitrile derivatives

ABSTRACT

Compounds of the formula PROTECT THE LIVER AGAINST THE ACTION OF CARBON TETRACHLORIDE WITH-OUT EXHIBITING ANY SIDE EFFECTS.

0 United States Patent [I51 3,679,730 Irikura et al. 1 July 25, 1972 [54] AMINOACETONITRILE DERIVATIVES 5 I] 1m. Cl "con 121 52 [72] Inventors: Tsutomu Irikura; Keigo Nishino; seigo [58] Held of Search ..260/465 D zue, all of Tokyo; Keiichi Ushiyama, Saitama-ken; l-lirotaka Shinoda, [56] References Cited Kawaguchi-shi; Yoshinori Hasegawa, Tokyo, all of Japan ,4 91 969 t l. ..260 465 [73] Assignee: Kyorin Seiyaku Kabushiki Kaisha, Tokyo, 3 67 6 9/] lnkum e a D Japan Primary Examiner-Joseph P. Brust [22] Filed: April 21, 1969 Altorney-Wenderoth, Lind & Ponack Related U.S. Application Data Compounds f the f l [62] Division of Ser. No. 558,281, June 17, 1966, Pat. No.

3,462,533. @NIICHz-CONHCH1CN COOH [30] Foreign Application Priority Data protect the liver against the action of carbon tetrachloride June 18, 1965 Japan ..40/36289 without exhibiting any side ff a [52] U.S. Cl. ..260/465 D, 260/2949 4 Claims, No Drawings AMINOACETONITRILE DERIVATIVES This application is a division of Ser. No. 558,281, filed June 17, 1966, now US. Pat. No. 3,462,533.

This invention relates to novel compounds which are expressed by the following general formula:

COOH (1) wherein the carboxyl group is in the o-, mor p-position of the benzene ring.

Aminoacetonitrile is known to prevent liver damage caused by liver-damaging substances such as carbon tetrachloride, bromobenzene, thioacetamide, etc. Its use therapeutically is, however, effectively excluded because of the harmful pharmacological side effects bound up with such use.

According to the present invention, the compounds 1 are useful to achieve the desired liver protecting action against carbon tetrachloride and the like, while being free of the aforesaid harmful side effects. Furthermore, the use of the compounds 1, as liver protecting agents, is not accompaniedas is sometimes the case with other substances used for the said purpose-by the appearance of lathyrism, especially bone lathyrism. This improvement, according to the present invention, appears to be ascribable to the fact that the amino acid moiety of the compound 1 contains not naturally occurring amino and carboxyl groups.

The improved action vis-a-vis for example carbon tetrachloride is demonstrated in the following table, by way of illustration; by the effect on liver function achieved in the rat with e.g. N-( N-(p-carboxyphenyl)-glycyl )aminoacetonitrile.

etc., is preferred, a weakly alkaline substance, such as magnesium oxide for example, being the best. Water is the best solvent, but alcohols and pyridine can also be employed.

An efieetive dose of a compound 1 or pharmaceutically acceptable salt thereof, is administered, (e.g., orally or by injection (intravenous, intramuscular, subcutaneous) in an amount of about 600 mg to about 1,200 mg per day, and is repeated as required depending upon frequency and extent of exposure to liver damaging agents.

The following examples are shown for the purpose of illustration.

EXAMPLE I N-( N( p carhoxyphenyl )glycyl )aminoacetonitrile 13.7 grams of p-aminobenzoic acid, 13.2 grams of chloroacetylaminoacetonitrile and 2 grams of magnesium oxide were suspended in 130 milliliters of water. The mixture was gently refluxed, became clear in a short time and crystals separated out in about one hour. After being heated for 2 hours, the mixture was cooled to room temperature (about 25) and the crystals were filtered off. Recrystallization from a large amount of hot water gave 9.7 grams of white lamella crystals having a melting point of 21421 7 C. Analysis: Cale: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.55; H, 4.58; N, 17.85.

EXAMPLE2 N-( N-( o-carboxyphenyl )glycyl )aminoacetonitrile 1.3 grams of anthranilio acid, 1.3 gram of chloroacetylaminoacetonitrile and 0.2 gram of magnesium oxide were reacted in 13 milliliters of water for 2 hours at 100C. White needles, which separated on cooling, were fil- (In H00 CNHCHz-CONHCH2CN TABLE Blood Blood serum Ratio Number serum Ratio Number Group GOT 1 (percent) of rats GPI (percent) 01 rats Carbon tetrachloride administered 25,000 100 2 35,300 100 2 Compound Ia of this invention adminstared:

mgJkg. 4, 133 16. 4 3 G, 067 17. 1 3 100 mgJkg 3, 400 13.0 3 600 27 3 200 mg./kg 2, 600 10. 4 3 7, 400 21 3 1 Blood serum GOT means glutamic oxalotransaminase in blood serum.

2 Blood serum GP'I means glutamic pyruvie transaminuso in blood Surt It is seen from the foregoing results that the compound la of this invention reduces the escape of liver enzymes into the blood, as compared with carbon tetrachloride, hence protects against liver trouble due to the latter. Still better is the fact that there is observed no or only such minimal lathyrism as can therapeutically be ignored.

Essentially analogous effects are observed with the corresponding oand m-substituted analogs of compound la.

The compounds of this invention can best be prepared by the process of the following general reaction scheme:

(11) (Ill) HO O C (I) wherein X indicates a halogen atom. In other words, they are prepared by the reaction of amino acid (11) with N-( halogenacetyl)aminoacetonitrile (111). Instead of the free carboxy compound 11, use may also be made of the alkali metal salts (e.g., sodium salts, potassium salts, lithium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesiumsalts, etc.) or salts with organic bases (e.g., amine salts, pyndlnrum salts,

etc. whereby the corresponding salts of compound 1 are obtained. Alkali metal salt of the amino acid is preferably used instead of free acid. In case the free acid is used, the presence of basic substances such as, for example, alkali metal hydroxide, alkali metal carbonate, alkali metal oxide, tertiary amine,

tered off. Recrystallization from hot water gave 0.9 gram of white needle crystals of M.P. 210-21 1C.

EXAMPLE 3 and pharmaceutieally acceptable alkali metal and alkaline earth metal, salts thereof.

2. The compound of claim 1 in which the COOH group is in p-position.

3. The compound of claim 1 in which the COOH group is in o-position.

4. The compound of claim 1 in which the COOH group is in m-position. 

2. The compound of claim 1 in which the COOH group is in p-position.
 3. The compound of claim 1 in which the COOH group is in o-position.
 4. The compound of claim 1 in which the COOH group is in m-position. 